Abstract | PURPOSE:
Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures. We previously found that intracerebral administration of interleukin-1 (IL-1)-beta has proconvulsant effects, whereas its endogenous receptor antagonist (IL-1Ra) mediates potent anticonvulsant actions in various models of limbic seizures. In this study, we investigated whether seizures can be effectively inhibited by blocking the brain production of IL-1beta, by using selective inhibitors of interleukin-converting enzyme ( ICE/ caspase-1) or through caspase-1 gene deletion. METHODS: RESULTS: Caspase-1 inhibition reduced the release of IL-1beta in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 microg) or VX-765 (intraperitoneal, 25-200 mg/kg) to rats blocked seizure-induced production of IL-1beta in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration. Mice with caspase-1 gene deletion showed a 70% reduction in seizures and an approximate fourfold delay in their onset. CONCLUSIONS: Inhibition of caspase-1 represents an effective and novel anticonvulsive strategy, which acts by selectively reducing the brain availability of IL-1beta.
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Authors | Teresa Ravizza, Sian-Marie Lucas, Silvia Balosso, Liliana Bernardino, George Ku, Francesco Noé, Joao Malva, John C R Randle, Stuart Allan, Annamaria Vezzani |
Journal | Epilepsia
(Epilepsia)
Vol. 47
Issue 7
Pg. 1160-8
(Jul 2006)
ISSN: 0013-9580 [Print] United States |
PMID | 16886979
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anticonvulsants
- Azepines
- Caspase Inhibitors
- Interleukin-1
- Isoquinolines
- Prodrugs
- Protease Inhibitors
- Pyridazines
- Caspase 1
- pralnacasan
- Kainic Acid
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Topics |
- Animals
- Anticonvulsants
(pharmacology)
- Azepines
(pharmacology)
- Brain
(drug effects, enzymology, metabolism)
- Caspase 1
(genetics)
- Caspase Inhibitors
- Disease Models, Animal
- Hippocampus
(drug effects, metabolism)
- Interleukin-1
(antagonists & inhibitors, metabolism)
- Isoquinolines
(pharmacology)
- Kainic Acid
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Prodrugs
(pharmacology)
- Protease Inhibitors
(pharmacology)
- Pyridazines
(pharmacology)
- Rats
- Seizures
(chemically induced, metabolism, prevention & control)
- Tissue Culture Techniques
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